16, 17-acetal and ketal derivatives of 16alpha, 17alpha-dihydroxy-21-halo steroids of the pregnane series



United States Patent Patented Sept. 11, 1962 Oil 3,053,838 16,17-ACETAL AND KETAL DERIVATIVES OF 160:, 17u-DIHYDROXY-21-HALO STEROIDS OF THE PREGNANE SERIES Josef Fn'ed, Princeton, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Nov. 7, 1958, Ser. No. 772,404

11 Claims. (Cl. 260-43955) ornz wherein the 1,2-position is saturated or double-bonded; R is hydrogen, R is fi-hydroxy or together R and R is keto; X and X are hydrogen, halogen (i.e. fluoro, chloro, bromo and iodo), or lower alkyl, at least one X being hydrogen or lower alkyl; Y is hydrogen or methyl; Y is halogen (i.e. fluoro, chloro, bromo, and iodo); Z is halogen (i.e. fluoro, chloro, bromo, and iodo), P and Q are hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, 'monocyclic heterocyclic, or monocyclic heterocyclic lower alkyl; or together with the carbon atom to which they are joined P and Q are cycloalkyl or monocyclic heterocyclic.

The final products of this invention are prepared by interacting a steroid of the general formula wherein the 1,2-position is saturated or double-bonded;

fined, With an alkane or aryl sulfonyl halide (sulfonyl chlorides being preferred, although other halides such as bromides and iodides may be used) to yield the new 21- alkane (or alkyl) sulfonyloxy intermediates of this invention, Although any alkane (or aryl) sulfonyl chloride may be used, the alkane group is preferably a lower alkane, methanesulfonyl chloride (mesyl chloride) being particularly preferred, and the aryl group is preferably p-tolyl. The reaction is carried out by intermixing the ZI-hydroxy steroid and sulfonyl halide under substantially anhydrous conditions and preferably in the cold (e.g. a temperature less than about 'C.), in the presence of pyridine or other organic tertiary base. As stated before, the reaction results in the new 21-alkane (or aryl) sulfony-loxy compounds of this invention, particularly steroids of the following general formula CHzOSOzR" wherein the 1,2 position is saturated or double-bonded; R, R, X, X, Y, Y, P and Q are as hereinbefore defined, and R is preferably lower alkyl or tolyl.

These 21-alkane (or aryl) sulfonyloxy inter-mediates are then reacted with a 'metal halide (such as an alkali metal halide, particularly potassium bifluoride, potassium fluoride, lithium chloride, lithium bromide and sodium iodide) in an organic solvent. The reaction is conducted at an elevated temperature (e.g. at reflux), under substantially neutral conditions. The reaction results in the production of new 21-halo steroids of this invention having the general formula wherein the 1,2 position is saturated or double-bondedf and R, R, X, X, Y, Y, Z, P and Q are as hereinbefore defined. Among the suitable starting steroids utilizable in the process of this invention may be mentioned the l6 ,l7 acetal and ketal derivatives of 6a-halo-l6u-hydroxyhydrocortisone (e.g. 6tr-fiuoro-l6othydroxyhydrocortisone), 6a-halo-l6a-hydroxycortisone, 6a-halo-l'a-hydroxyprednisolone, 6a-halo-l6m-hydroxyprednisone, 6 a,9u-dihalo-l6a-hydroxyhydrocortisone (e.g. 6u,9a-didiuoro-l6a-hydroxyhydrocortisone), 1

6a,9adihalo-16a-hydroxycortisone, 6a,9a-dihalo-16u-hydroxyprednisolone (e.g. 6a,9a-difiuoro-l6a-hydroxyprednisolone), 6a,9a-dihalo-l6a-hydroxyprednisone, Zen-methYl-fia-flHOI'O-16oc-hYdI'OXYhYdIOCOIfiSOIlC, 2a-methyl-6a-fluoro-l6u-hydroxycortisone, 6ot-ha10-9a-(lOWer alkyl)-'16a-hydroxyhydrocortisone (e.g.

6a-fiuoro-9a-methyl-16u-hydroxyhydrocortisone), 6 a-hfllO-Qa- (lower alkyl l-6u-hydroxycortisone, 6a-halo-9a-(lower alkyl)-16a-hydroxyprednisolone, 6a-halo-9 a- (lower alkyl) -1 6a-hydroxyprednisone, 6tx,9a-dihalo-12u-(lower alkyl) -16a-hydroxyhydrocortisone (e.g. 6at,9vt-difiuoro-1:2ot-methyl-16nt-hydroxyhydrocortisone) 60:,9ot-dih2il0- 1 (lower alkyl)-16a-hydroxycortisone, 6a,9a-dihalo-12m(lower alkyl)-16a-hydroxyprednisolone (e.g. 6u-chloro-9a-fluoro1Za-methyl-l 6a-hydroxyprednisolone), 6a,9a-dih alo- 1 2a- (lower alkyl) -1'6a-hydroXyprednisone, 6m,12a-dihalo-16a-hydroxyhydrocortisone (e.g. 6a,l2a-difluoro-16a-hydroxyhydrocortisone and 6a-chloro-12afluoro-1-6a-hydroxyhydrocortisone) 6a,12a-dihalo-l6a-hydroxycortisone (e.g. 6a-fluoro-12achloro-l6a-hydroxycortisone, 6a, l2ix-dichloro-l6a-hydroxycortisone, and 6u,12-difluoro-16u-hydroxycortisone), 6a,12a-dihalo-16u-hydroxyprednisolone (e.g. 6a,12 x-difluoro-l6a-hydroxyprednisolone, and 6a-Chl0IO-l2afluOI'O-16a-hYdl'OXYPI6dI1iSOlOHC), 6a,IZa-dihalo-l6ot-hydroxyprednisone (e.g. 60t-flUOI'O-120tchloro-1'6a-hydroxyprednisone) 2ct-methyl-6a,l2a-dihalo-16a-hydroxyhydrocortisone (e.g. 2a-rnethyl-6a, 1 Za-difiuoro- 1 Ga-hydroxyhydro cortisone 2at-methyl-6oqlZa-dihalo-l6a-hydroxycortisone, 2-methyl-6u, 12ot-dihalo-1 6a-hydroxyprednisolone, and Z-methyhfioz, 12u-dihalo-16u-hydroxyprednisone,

with lower alkanals, such as paraldehyde, propanal, and hexanal; halogenated lower alkanals, such as chloral hydrate trifluoroacetaldehyde hemiacetal and hepta fluorobutanal ethyl hemiacetal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; halogenated di(lower alkyl)ketones, such as 1,1,1-trifiuoroacetone; cycloalkanones, such as cyclopentanone, cyclohexanone, suberone, cyclobutanons, and cyclodexanone; mono and dicycloalkyl ketones, such as cyclohexylmethyl ketone and dicyclopropyl ketone; monocyclic aromatic aldehydes, such benzaldehyde,

halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fluorobenzaldehyde) lower alkoxy benzaldehydes (e. g. o-anisaldehyde) di(lower alkoxy) benzaldehydes (e.g. veratraldehyde),

hydroxybenzaldehydes (e.g. salicylaldehyde),

dihydroxybenzaldehydes (e.g. resorcylaldehyde) lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde) di(lower alkyl)benzaldehydes (e.g. o,p-dimethylbenzaldenitrobenzaldehydes,

acylamidobenzaldehydes (e.g. N-acetylanthranilaldehyde), and

cyanobenzaldehydes;

monocyclic aromatic lower alkanals, such as phenylacetaldehyde, ot-phenylpropionaldehyde, fl-phenylpropionaldehyde, 'y-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives thereof; mono- 4 cyclic heterocyclic lower alkanals; monocyclic aromatic lower alkyl ketones, such as acetophenone,

propiophenone,

butyrophenone,

valerophenone,

isocaprophenone,

halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone) (lower alkoxy)phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone),

di(lower alkoxy)phenyl lower alkyl ketones,

hydroxyphenyl lower alkyl ketones,

dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone),

(lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone),

di(lower alkyl)phenyl lower alkyl ketones (o,p-xylyl methyl ketone),

nitrophenyl lower alkyl ketones (e.g. p-nitroacetophenone),

acylamidophenyl lower alkyl ketones (e.g.acetylanilines),

and

cyanophenyl lower alkyl ketones;

benzophenone, and mono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic aromatic lower alkanones, such as 1-phenyl-3-butanone and 1-phenyl-4- pentanone, and aromatically substituted derivatives thereof; monocyclic heterocyclic ketones, such as 2-acetylfuran, 2-benzoyl furan, and Z-acetylthiophene; monocyclic heterocyclic lower alkanones; and monocyclic heterocyclic ketones, such as alloxan.

The starting steroids can be prepared by the methods disclosed in my US. applications, Serial No. 677,205, filed August 9, 1957, now abandoned; 753,401, filed August 6, 1958; and 764,495, filed October 1, 1958. In those cases wherein the lfia-hydroxy steroid employed in the acetalization or ketalization process of these applications is new, it can be prepared microbiologically from the corresponding 16-unsubstituted steroids by action of Streptomyces roseochromogenus, for example, in accordance with the method described in the US. Patent No. 2,855,343, granted October 7, 1958.

All of the final 21-halo products of this invention are physiologically active substances which possess glucocortiooid and anti-inflammatory activity and hence can be used topically in lieu of known glucocorticoids and antiinflammatory agents such as hydrocortisone in the treatment of skin conditions such as dermatitis, sunburn, neurodermatitis, eczema, and anogenital pruritus.

The following examples are illustrative of the invention (all temperatures being in centigrade). The first four examples are directed to and illustrate methods for the preparation of the intermediate 21-alkane (or aryl) sulfonyloxy derivatives. The following examples illustrate methods for the preparation of the 21-halo final products of this invention.

EXAMPLE 1 Triamcinolone Acetonz'de ZJ-Mesylate To a solution of l g. of triamcinolone acetonide in 10 ml. of anhydrous pyridine is added at 0 1 ml. of methanesulfonyl chloride. After two hours at 0 ice Water is added and the precipitated mesylate is removed by filtration. The precipitate is washed thoroughly with water and dried in vacuo, and recrystallized from acetone-hexane. The pure mesylate has the following properties: M.P. about 248-250 (dec.) or 286-287 (dec.) (polymorphie forms). [a] +92 (c., 1.12 in CHCl Analysis.Calcd. for C H O SF (498.55): C, 57.81; H, 6.27; F, 3.81; S, 6.43. Found: C, 57.87; H, 6.20; F, 3.83; S, 6.33.

Similarly, by substituting aryl sulfonyl chlorides or other lower alkanesulfonyl chlorides for the methane sulfonyl chloride in the procedure of Example 1, the corresponding 21-arylsulfonyloxy and 21-alkanesulfonyloxy derivatives are formed. Thus, p-toluenesulfonyl chloride, ethanesulfonyl chloride and propanesul-fonyl chloride yield triamcinolone 21-p-toluenesulfonate, triamcinolone acetonide 21-ethanesulfonate and triam cinolone acetonide 2l-propanesulfonate, respectively.

EXAMPLE 2 16u-Hydr0xy-9a-Fluorohydrocortisone Acetonide 21 -Mesylate To a solution of 1.5 g. of 16a-hydroxy-9a-fluorohydrocortisone acetonide in ml. of dry pyridine is added at 0", 1.5 ml. of methanesulfonyl chloride. After standing in the refrigerator for 2% hours excess methanesulfonyl chloride is destroyed by the addition of a small amount of ice, after which ice-water is added slowly to precipitate the reaction product. After /2 hour in the refrigerator the material is filtered off, washed thoroughly with water and dried in vacuo. The resulting crude material after recrystallization from acetone-hexane gives the pure 2l-mesylate of the following properties: M.P. about 225-227 (dec.); [a] |-1l2 (c. 0.5 in chlf.);

ANujOl Analysis.-Calcd. for C H O FS (500.56): C, 58.35; H, 6.85; S, 6.23. Found: C, 58.18; H, 6.82; S, 6.05.

EXAMPLE 3 6a-Fluorotriamcinolone Acetonide 21-Mesylate EXAMPLE 4 6a-Chlor0triamcin0lone Acetonide 21-Mesylate Following the procedure of Example 2 but substituting 1.5 g. of 6a-chlorotriamincinolone acetonide for the 161%- hydroxyfiuorohydrocortisone acetonide, there is obtained 6a-chlorotriamcinolone acetonide 2l-mesylate.

Similarly, but substituting other 16a,17u-acetals or ketals for the triamcinolone acetonide in Example 1 or the 9a-iluoro-16u-hydroxyhydrocortisone acetonide in Example 2, the corresponding 21-mesylates are formed. Thus, triamcinolone acetophenone, 16a,17a-(2'-butylidene), 16a,17a-(.2'-butylidene) 6a-fluorotriamcinolone, 16m,l7a-(4-methyl-2-pentylidene) 60c fluorotriamcinolone, 160:,17tx-CYC10116XY11d6D6 6a -fluorotriarncinolone, 16u,17a-ethylidene 6oz fluorotriamcinolone, 6u,9a difluoro-l6u-hydroxyhydrocortis0ne acetonide, 6a-fluoro- 9u-methyl-l6u-hydroxyprednisolone acetonide, 6u,9adlflllOl'O-IZOL methyl-16a hydroxyhydrocortisone acetonide, 6a,9u-difiuor-o-12ot-methyl-l6a-hydroxyprednisolone acetonide, 6a-fluorotriamcinolone acetophenone, 6w fiuoro 16a hydroxyhydrocortisone benzaldehyde, 6afluorotriamcinolone l6u,l7a-alloxan, 6u-fluorotriamcinolone dicyclopropyl ketone, 6oL-flllOIO-12a-Ch1OI'O-l6ochydroxycortisone acetonide, 611,120: dichloro 16a hydr-oxycortisone acetonide, 6a,12a-difluoro-16a-hydroxycortisone acetonide, Got-fillOIO-120t-ChlOI'O-160t-hydI'OXy prednisone acetonide, 6a,l2-difiuoro 16a hydroxyprednisolone acetonide, 6a,12a-difiuoro-2a-methyl-l6a-hydroxyhydrocortisone acetonide, Got-fillOl'O-lZoc-ChlOIO-lGahydroxycortisone 16a,l7a-chloral, l6a,l7a- (1,1,l-trifluoroisopropylidene) 60c-fillOIO-120L-ChlOI'O-160t-hYdl'OXY- cortisone, and 6oz,lZzx-diflllOrO-lGot-hYdfOXYhYdIOCOIfisone benzaldehyde yield their respective 2l-1ne'sylate deri-vatives.

6 EXAMPLE 5 21-I0d0-9a-Fluor0-A -Pregnadiene-1 1fl,16oc,1 7a-Triol- 3,20-Di0ne 16a,17u-Acet0nide A solution of 500 mg. of triamcinolone acetonide 21- mesylate and 1.5 g. of sodium iodide in 15 ml. of acetone is refluxed for 40 hours. The reaction mixture is then diluted with water and the crystals filtered 011 and dried in vacuo. After recrystallization from acetone-hexane, pure 21-iodo-21-desoxytriamcinolone acetonide has the following properties: M.P. about 176-178 (dec.); [a] -{'l3 (c. 1.12 in CHCI Analysis.-Calcd. for C H O FI (544.40) C, 52.94; H, 5.55; I, 23.31. Found: C, 52.31; H, 6.02; I, 22.69.

EXAMPLE 6 21-I0d0-9a-Fluoro-A -Pregnene-115,16 7u-Tri0l- 3,20-Di0ne J 6 11,1 7 a-Acetonide A solution of 250 mg. of 9u-fluoro-16a-hydroxyhydrocortisone l6a,l70a-&Ct0l1id6 2l-rnesylate and 750 mg. of sodium iodide in 7 ml. of acetone is refluxed for 40 hours, the resulting reaction mixture diluted with water and the resulting crystals filtered, Washed well with water and dried in vacuo. Recrystallization of the crude product from acetone-hexane furnishes the pure iodo compound possessing the following properties: M.P. about 173-175 (dec.); [a] (c. 0.52 in chloroform);

EXAMPLE 7 Following the procedure of Example 6, but substituting 250 mg. of 6a-fluorotriamcinolone 16u,17u-acetonide 21- mesylate for the 9a-fiuoro-16a-hydroxyhydrocortisone 16a,17a-acetonide 21-mesylate, there is obtained 21-iodo. 60,9a difluoro A -pregnadiene-l1p,16a,17a-triol-3,20- dione 16a,l7a-a-cetonide.

EXAMPLE 8 EXAMPLE 9 A mixture containing 1 gm. of triamcinolone acetonide 21-mesylate, 1 gm. of KF and 25 ml. of ethylene glycol is refluxed for 19 hours. The dark solution is poured into ice-water, extracted with chloroform and the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from acetone with the aid of charcoal. The pure fluoride after three crystallizations has the following properties: M.P. about 310;

Analysis.Calcd. for (3 11 0 1 (436.48): C, 66.04; H, 6.93; F, 8.59. Found: C, 65.64; H, 6.93; F, 7.81. 1

This compound possesses about 29 times the activity of cortisone in the rat liver glycogen assay and about 20 times the activity of hydrocortisone in the rat antiinflammatory assay.

7 EXAMPLE 10 21-Chl0r0-9u-Flu0r0-A -Pregnadiene-I 1133 160:170;- Tril-3,20-Di0ne 16,1 7-A cetonide A solution of 200 mg. of triamcinolone acetonide 21- mesylate and 900 mg. of lithium chloride in 25 ml. of dimethylformamide is kept at 100 for 24 hours. The mixture is poured on ice, extracted with chloroform and the chloroform extract washed with water and dried over sodium sulfate. Evaporation of the solvent in vacuo furnishes the crystalline chloride, which after recrystallization from acetone-ethanol has the following properties: M.P. about 310.

Analysis-Calm. for C H O FCl (454.96); C, 63.35; H, 7.09; Cl, 7.99. Found: C, 63.31; H, 6.83; Cl, 7.92.

When the lithium chloride in the above reaction is replaced by lithium bromide and the reaction is shortened to 12 hours there is obtained the corresponding 21-bromo derivative.

EXAMPLE 11 Following the procedure of Example 9, but substituting 1 g. of 6a-fluorotriamcinolone l6a,l7a-acetonide 21- mesylate for the triamcinolone acetonide 2l-mesy1ate, there is obtained 6a,9a,21-trifluoro-A -pregnadiene-l113, 16a,17oc-tl'iOl-3,20-dl01l 16a,17a-acetonide.

EXAMPLE l2 6a-Chl0r0-9a,21-Difluoro-A -PregnadieneJ1,8,16a, 1 7 a-Tri0l-3,20-Di0l1e 16a, 1 7a-A cetonide Following the procedure of Example 9, but substituting l g. of 6a-chlorotriamcinolone 16u,17u-acetonide 21- rnesylate for the triamcinolone acetonide 2l-mesylate, there is obtained 6a-chloro-9a,2l-difluoro-A -pregnadiene-ll5,l6u,l7a-triol-3,20-dione 16x,17a-acetonide.

Similarly by substituting the 2l-mesylates of 160:,17ot- (2-butylidene) 6a-fluoro triamcinolone, 16a, 1 7a 4-rnethyl-2-pentylidene) 6afiuoro-triamcinolone, 16a,17a-cyclohexylidene 6u-fiuorotriamcinolone, 16a,l7x-ethylidene 6a fiuorotriamcinolone, 6a,9a difluoro-16whydroxy-hydrocortisone acetonide, 6m-fiuoro-9a-methyl-l6u-hydroxyprednisolone acetonide, 6a,9a-difiuoro-12a-methyl-16ahydroxyhydrocortisone acetonide, 611,911 difiuoro -12umethyl-l6u-hydroxypredniso1one acetonide, the acetophenone derivative of 6 -fiuorotriamcinolone, 16a,17abenzylidene, 6wfluoro-l6a-hydroxyhydrocortisone, the alloxan derivative of 6a-fiuorotriamcinolone, the dicyclopropyl ketone derivative of 6a-fluorotriamcinolone, 6afluoro-l2a-chloro-l6a-hydroxycortisone acetonide, 604,120:- dichloro-l6a-hydroxycortisone acetonide, 6a,l2a-chloro- 16a-hydroxyprednisone acetonide, 6a,12-difluoro- 160chydroxyprednisolone acetonide, 6a,l2a-difluoro-2a-methyl 160: hydroxyhydrocortisone acetonide, 160:,170: trichloroethylidene, Goa-fluoro-1Zen-chloro-16a-hydroxycortisone, 16oc,17 a- 1,l,1-trifluoroisopropylidene) 6 lZ'flllOI'O- 12a-chloro-lfia-hydroxycortisone, and l6a,17a-benzylidene, 6a,IZa-difiuoro-lGwhydroxyhydrocortisone for the triamcinolone acetonide ZI-mesylate in Examples 9 and 10, the respective 2l-fiuoro and 21 chloro derivatives are obtained.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

l. 6a-halotriamcinolone acetonide 21-(lower alkane) sulfonate.

2. fiu-fiuorotriamcinolone acetonide 21-mesylate.

3. Ga-ChlOrotfiamciIlOlOnB acetonide 21-n1esylate.

4. 21-halo-6a,9a-difiuoro-A -pregnadiene-1 1fi,16a,17atriol-3,20-dione 16a,17a-acetonide.

5. 21-halo-6a-chloro 9a fiuoro-A -pregnadiene11B, 16a,17a-triol-3,20-dione 16a,17a-acetonide.

6. 6a,9a,21 trifluoro-A -pregnadiene 115,161,170;- tri0l-3,20 dione l6a,l7a-acetonide.

8 7. 6a-chloro-9a,21-difluoro A -pregnadiene 115,160, l7a-triol-3,20-dione l6a,17a-acetonide.

8. A compound selected from the group consisting of steroids of the general formulae OHzOSOzR" wherein R is hydrogen, R is [i-hydroxy and together R and R is keto; R" is selected from the group consisting of p-tolyl and lower alkyl; X and X are selected from the group consisting of hydrogen, halogen and lower alkyl, at least one X being selected from the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of hydrogen and methyl; Y is halogen; P and Q are selected from the group consisting of hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic.

9. A compound selected from the group consisting of steroids of the general formulae and sisting of hydrogen, halogen and lower alkyl, at least one X being selected from the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of hydrogen and methyl; Y and Z are halogen; and P and Q are selected from the group consisting of hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl and together with the carbon to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic.

10. A process for preparing a steroid of claim 8 which comprises interacting the corresponding steroidal compound selected from the group consisting of steroids of the general formulae and wherein R, R, X, X, Y, Y, P and Q are as defined in claim 8, with a compound selected from the group consisting of a lower alkane sulfonyl halide and p-toluene sulforiyl halide under substantially anhydrous conditions, and recovering the steroid formed.

11. A process for preparing a steroid of claim 9, which comprises interacting the corresponding steroidal com- 10 pound selected from the group consisting of steroids of the general formulae OHzOSOzR I in wherein R is hydrogen, R is ,B-hydroxy and together R and R is keto; R is selected from the group consisting of p-tolyl and lower alkyl; X and X' are selected from the group consisting of hydrogen, halogen, and lower alkyl, at least one X being selected from the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of hydrogen and methyl; Y is halogen; P and Q are selected from the group consisting of hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic; with a metal halide at an elevated temperature under substantially neutral conditions, and recovering the steroid formed.

References Cited in the file of this patent UNITED STATES PATENTS 

9. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE GENERAL FORMULAE 